Intracellular receptors are a class of structurally related proteins involved in the regulation of gene proteins. Steroid receptors are a subset of these receptors, including the glucocorticoid receptor (GR), progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), and mineralocorticoid receptor (MR). Regulation of a gene by such receptors or factors requires the intracellular receptor and a corresponding ligand which has the ability to selectively bind to the receptor in a way that affects gene transcription.
The current steroidal glucocorticoid receptor modulators (glucocorticoids) like prednisolone a.o. are very effective anti-inflammatory agents that are currently used to treat diseases like Rheumatoid Arthritis (RA), Inflammatory Bowel Disease (IBD), Lupus, allergies, asthma, psoriasis and to prevent transplant rejection (J. D. Baxter, Advances in Internal Medicine 45; 317-349; 2000). Anti-inflammatory effects of these compounds are thought to be mediated through an inhibition of the expression of pro-inflammatory mediators like adhesion molecules, cytokines, chemokines and enzymes by a mechanism that involves the interaction of the ligand-bound GR with transcription factors. This mechanism is referred to as transrepression (M. Karin, Cell 93; 487-490; 1998).
The use of current steroidal glucocorticoids is accompanied by metabolic and other side effects (e.g. diabetes, hypertension, osteoporosis, muscle wasting, a.o.). Part of these side effects are thought to be mediated through the direct interaction of the ligand bound GR to glucocorticoid responsive elements (GRE's) on the DNA of target genes and the subsequent induction of gene expression (J. D. Baxter, Advances in Internal Medicine 45; 317-349; 2000; M. Karin, Cell 93;487-490; 1998). Another part of these side effects might be due to cross-reactivity with other steroidal receptors, like the mineralcorticoid (MR) or the progesterone receptor (PR).
Non-steroidal glucocorticoids have no molecular structural similarity with steroids and therefore one might also expect differences in physicochemical properties, pharmacokinetics (PK) parameters, tissue distribution (e.g. CNS versus peripheral) and more importantly non-steroidal glucocorticoids may show no/less cross-reactivity to other steroid receptors or may show no/less metabolic or other side effects.